Is PMS2 p.Pro440Ala (c.1318C>G) pathogenic?

PMS2 p.Pro440Ala (c.1318C>G) is classified Uncertain significance in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.0557); Very rare (popmax 0.00668%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Pro440Ala (c.1318C>G)?

PMS2 p.Pro440Ala (c.1318C>G) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Pro440Ala (c.1318C>G) in the general population?

PMS2 p.Pro440Ala (c.1318C>G) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about PMS2 p.Pro440Ala (c.1318C>G)?

AlphaMissense predicts likely benign (score 0.0557) — an in-silico prediction, not a clinical call.

PMS2 p.Pro440Ala

c.1318C>G · rs762894051 · VCV233783

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0557 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0557	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -6.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.89	phastCons 0.004
Regional constraint	o/e 1.09	unconstrained · MANE · 22 kb · p 0.015 · regional, not allelic
Overall
CADD	0.118	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,880 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000186% 3/1,614,128 alleles · very rare exomes 3/1,461,820 · genomes 0/152,308 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PMS2
Protein: p.Pro440Ala
Coding: c.1318C>G
MANE Select: NM_000535
dbSNP: rs762894051
Type: single nucleotide variant
Location: chr7:5987447 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 440: the 'disordered' region

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4

Similar variants

PMS2 p.Pro440Arg Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro440Thr Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro440= Benign/Likely benign ★★ same residue
PMS2 p.Pro440Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Pro440Ser Uncertain significance ★ ⚠ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pms2-p-pro440ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown